Although there are effective psychotherapies for combat-related PTSD, symptoms persist for some veterans even after treatment. Identifying biological alterations associated with treatment response is essential to treatment development and can be accomplished through longitudinal evaluation. Longitudinal assessments permit a distinction between recovery, persistence, and resistance to the development of PTSD. This proposal aims to identify molecular and endocrine diagnostic and prognostic biomarkers associated with PTSD and recovery by comparing biological markers in 60 OIF/OEF/OND veterans with PTSD before and after treatment with cognitive processing therapy (CPT-C). The direct manipulation of PTSD symptoms over the course of 12 weeks of psychotherapy will result in a sample with a variable range of symptom improvement. At treatment end, the PTSD group will be subdivided into those no longer meeting DSM-V criteria for PTSD and those who still have PTSD. 30 veterans exposed to similar levels of combat, but who never developed PTSD will also be studied at two times, 12 weeks apart. It will therefore be possible to determine 1) whether, and in what way combat veterans who recover following psychotherapy differ biologically from those who fail to recover, and 2) whether, and in what manner those who recover are similar to those who never developed PTSD, at pre and/or post-treatment. We propose to measure specific candidate biomarkers, but also use genome-wide methods to screen for a broader array of relevant genes and biological pathways. The candidate biomarkers associate with glucocorticoid receptor (GR) responsiveness. Previous work has implicated GR functioning and cortisol signaling in association with PTSD risk, diagnosis and symptom severity. Genotype, methylation status and gene expression of two genes, NR3C1 (the GR gene) and FK506 Binding Protein 5 (FKBP5; a critical modulator of GR activity) will be measured, as well as more downstream functional indices of GR responsivity as reflected by the in vitro lymphocyte lysozyme test, basal urinary cortisol levels and plasma neuropeptide Y (NPY). Simultaneously, we will screen for other relevant CpG Islands and genes using, respectively, the Illumina Infinium Human Methylation 450 BeadChip Kit and the Psych Chip. The approach of examining genotype, cytosine methylation (epigenetics), gene expression and GR functional endocrine outcomes provides a comprehensive assessment of critical regulators at multiple levels, so as to promote a detailed understanding of mechanisms of psychopathology and recovery, and will permit hypotheses to be generated regarding molecular antecedents of PTSD associated biology. Cytosine methylation of the promoter regions of the GR and FKBP5 genes are thought to reflect relatively enduring processes that can also be influenced by environmental factors that result in functional (e.g., endocrine) alterations. The endocrine measures representing downstream effects of GR have been previously demonstrated to change in association with symptom change. Comparison with a group of similarly exposed veterans who did not develop PTSD allows an examination of normative temporal stability of the biological measures, which has not been established in the field for molecular markers. An objective biological test predicting or correlating with recovery would have great clinical utility and would also yield important insights into PTSD pathophysiology. The association of variation in PTSD symptom severity with changes in epigenetic and gene expression measures relevant to PTSD is novel, and will facilitate the examination of biological and psychological variables associated with prognosis, diagnosis, and recovery, in the context of symptom change over time. This proposal represents a critical step the determination of whether the GR or its molecular scaffolding represent targets for PTSD prevention and treatment, and will further inform a model of PTSD etiology and chronicity in combat exposed veterans.